tbuckley/cabot-search huggingface dataset:
Body composition in patients with metastatic renal cell carcinoma receiving ipilimumab plus nivolumab.
Authors: Hannah Elizabeth Dzimitrowicz, Fides Schwartz, Jordan Infield, Dylan Zhang, Ethan Ho, Yuan Wu, Rajan T. Gupta, Michael Roger Harrison
Journal: Journal of Clinical Oncology (2022)

e16517 Background: Body composition (comp) is an increasingly recognized prognostic indicator in patients with cancer, but there are limited data regarding body comp measurements in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors. The goal of this study was to assess baseline body comp measurements and rates of sarcopenia in patients with mRCC receiving ipilimumab + nivolumab (ipi/nivo) as first-line systemic therapy and examine potential associations with overall survival (OS). Methods: We conducted a retrospective analysis of all patients with mRCC treated with first line ipi/nivo at Duke Cancer Center prior to June 1, 2021, who had a CT scan within 6 weeks of ipi/nivo initiation. CT images were segmented and measured with Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) software (Voronoi Health Analytics). Areas of skeletal muscle (SM), subcutaneous fat (SF), and visceral fat (VF) at the level of the 3rd lumbar vertebra were measured and converted to indices by dividing by height (m 2 ) (Area SMI, SFI, VFI). Volumes of SM, SF, and VF between the 1st and 5th lumbar vertebrae were measured and converted to indices by dividing by the height of the measured slab (Volume SMI, SFI, VFI). Sarcopenia was defined as SMI &lt; 55cm 2 /m 2 in men and &lt; 39cm 2 /m 2 in women based on prior studies. Medical records were retrospectively reviewed to identify demographic and oncologic details. Effects of body comp measures on overall survival were assessed using Cox proportional hazard models, which were adjusted for IMDC risk, age, and sex. Results: 104 patients met study criteria and had an analyzable baseline CT scan. Median age was 62 (range 37 – 81). 71% of patients were male. Median body mass index (BMI) was 27.2 (range 17.8 – 43.6). IMDC risk score was 12% favorable, 63% intermediate, 20% poor, and 5% unknown. Median follow up time was 19.98 months. Median survival was 39.79 months (95% CI 27.01, NA). 1-year survival rate was 0.81 [95% CI 0.73, 0.89] and 2-year survival rate was 0.68 [95% CI 0.59, 0.79]. 77 of 104 patients (74%) met the definition of sarcopenia prior to treatment. No body comp measurements were associated with OS. Effects of body comp measurements on overall survival are shown in table 1. Conclusions: Baseline body comp measures were not associated with OS in a population of patients with mRCC receiving ipi/nivo as first-line systemic therapy. Changes in body comp over time may instead be of interest as potential biomarkers for OS in patients with mRCC receiving ipi/nivo. [Table: see text]
Network analysis integrating microRNA expression profiling with MRI biomarkers and clinical data for prostate cancer early detection: A proof-of-concept study
Authors: M. Pecoraro, P. Paci, F. Conte, Z.M. Besharat, G. Catanzaro, E. Splendiani, A. Sciarra, L. Farina, E. Ferretti, V. Panebianco
Journal: European Urology (2022)
SURG-11. Evaluation of surgical results and predictive factors of hydrocephalus in pediatric patients with posterior fossa tumors
Authors: Cleiton Formentin, Leo Gordiano Matias, Lucas de Souza Rodrigues dos Santos, Erion Junior de Andrade, Andrei Fernandes Joaquim, Helder Tedeschi, Enrico Ghizoni
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Infratentorial tumors represent 45 to 60% of all brain tumors in children and are associated with hydrocephalus in 70 to 90% of cases. The aim of this study is to describe and analyze the surgical results and correlate them with the incidence of hydrocephalus, as well as identify predictive factors of hydrocephalus in patients underwent to a surgical treatment of posterior fossa tumors. METHODS: This is a retrospective observational study, based on demographic, clinical and radiological information of pediatric patients underwent to surgical resection of posterior fossa tumors by a single group between 2011 and 2019. RESULTS: We included 135 patients with a mean age of 7.56 years, mean follow-up of 35.7 months and overall survival of 18.8 months. Considering the histology, most tumors were pilocytic astrocytomas (34.1%), followed by medulloblastomas (27.4%) Total resection was achieved in 77.8% and tumor recurrence was observed in 16.2%. The rate of hydrocephalus was 36.3%, with most shunt procedures performed preoperatively. There was a high rate of complications associated with shunting (42.9%), mostly represented by infection (71.5%). Patients with hydrocephalus were younger (p = 0.001), showing a faster evolution between the onset of symptoms and diagnosis (p = 0.008). Tumor volume (p = 0.1) and location (p = 0.32) were not statistically significant for hydrocephalus, however, the presence of leptomeningeal disease (p = 0.001) was. The resection rate was also significant, with lesions totally resected showing the best results (p = 0.009). Regarding tumor histology, 33.3% of patients with medulloblastoma and 62.5% of patients with ependymoma were shunted. CONCLUSION: One third of children with posterior fossa tumors will require a shunt procedure. Some factors should guide the neurosurgeon during patient counseling and surgical planning to minimize the use of permanent shunts and avoid related complications.
CRISPR detection of circulating cell-free Mycobacterium tuberculosis DNA in adults and children, including children with HIV: a molecular diagnostics study
Authors: Zhen Huang, Sylvia M LaCourse, Alexander W Kay, Joshua Stern, Jaclyn N Escudero, Brady M Youngquist, Wenshu Zheng, Debrah Vambe, Muyalo Dlamini, Godwin Mtetwa, Lisa M Cranmer, Irene Njuguna, Dalton C Wamalwa, Elizabeth Maleche-Obimbo, Donald G Catanzaro, Christopher J Lyon, Grace John-Stewart, Andrew DiNardo, Anna M Mandalakas, Bo Ning, Tony Y Hu
Journal: The Lancet Microbe (2022)

BackgroundTuberculosis remains a leading cause of global mortality, especially for adults and children living with HIV (CLHIV) underdiagnosed by sputum-based assays. Non-sputum-based assays are needed to improve tuberculosis diagnosis and tuberculosis treatment monitoring. Our aim in this study was to determine whether ultrasensitive detection of Mycobacterium tuberculosis cell-free DNA (Mtb-cfDNA) in blood can diagnose tuberculosis and evaluate tuberculosis treatment responses.MethodsIn this molecular diagnostics study we analysed archived serum from two patient populations evaluated for tuberculosis in Eswatini and Kenya to detect Mtb-cfDNA, analysing serum from all individuals who had both sufficient serum volumes and clear diagnostic results. An optimised CRISPR-mediated tuberculosis (CRISPR-TB) assay was used to detect Mtb-cfDNA in serum at enrolment from adults and children with presumptive tuberculosis and their asymptomatic household contacts, and at enrolment and during tuberculosis treatment from a cohort of symptomatic CLHIV at high risk for tuberculosis, who provided longitudinal serum at enrolment and during tuberculosis treatment.FindingsCRISPR-TB identified microbiologically and clinically confirmed tuberculosis cases in the predominantly HIV-negative Eswatini adult cohort with 96% sensitivity (27 [96%] of 28, 95% CI 80–100) and 94% specificity (16 [94%] of 17, 71–100), and with 83% sensitivity (5 [83%] of 6, 36–100) and 95% specificity (21 [95%] of 22, 77–100) in the paediatric cohort, including all six cases of extrapulmonary tuberculosis. In the Kenyan CLHIV cohort, CRISPR-TB detected all (13 [100%] of 13, 75–100) confirmed tuberculosis cases and 85% (39 [85%] of 46, 71–94) of unconfirmed tuberculosis cases diagnosed by non-microbiological clinical findings. CLHIV who were CRISPR-TB positive at enrolment had a 2·4-times higher risk of mortality by 6 months after enrolment. Mtb-cfDNA signal decreased after tuberculosis treatment initiation, with near or complete Mtb-cfDNA clearance by 6 months after tuberculosis treatment initiation.InterpretationCRISPR-mediated detection of circulating Mtb-cfDNA shows promise to increase the identification of paediatric tuberculosis and HIV-associated tuberculosis, and potential for early diagnosis and rapid monitoring of tuberculosis treatment responses.FundingUS Department of Defense, National Institute of Child Health and Human Development, National Institute of Allergy and Infectious Diseases, University of Washington Center for AIDS Research, and the Weatherhead Presidential Endowment fund.
Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress).
Authors: Erika P. Hamilton, Ciara Catherine Maria O'Sullivan, Miguel Martin, Joohyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Veronique C Dieras
Journal: Journal of Clinical Oncology (2022)

TPS1108 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Clinical trial information: NCT05132582.
RARE-25. Primary Intracranial Ewing Sarcoma in a Child: Case Report
Authors: John Emmanuel Custodio, Ronnie Baticulon, Eric Paolo Palabyab, Jared Paul Golidtum
Journal: Neuro-Oncology (2022)

Abstract Ewing sarcoma is a rare childhood tumor which accounts for 3% of all pediatric malignancies. More so, primary intracranial involvement with meningeal attachment is even rarer, accounting for only 1% of all Ewing sarcoma. We report a case of a 5-year-old boy who presented with headache, vomiting, and left-sided weakness that rapidly progressed over a period of three months. Cranial MRI showed a 7.1 x 6.7 x 8.6 cm multilobulated, heterogeneously enhancing, mixed solid and cystic extra-axial tumor compressing the frontoparietal lobe and causing significant midline shift. It was attached to the falx and infiltrated the middle third of the superior sagittal sinus. We performed a large right frontoparietal craniotomy to excise the tumor. Because of massive bleeding from the tumor, only a subtotal resection was possible. The bone flap was left out. The patient was discharged fully awake but with right hemiplegia on the fourteenth post-op day. Histopathologic examination revealed a spindle cell neoplasm that exhibited diffuse membranous staining for CD99. Fluorescence in-situ hybridization confirmed EWSR1 gene rearrangement, consistent with Ewing sarcoma. Three months after his surgery, the patient subsequently received 56 Gy of radiation therapy. At twelve months post-op, he remains fully awake and is back in school. He has residual left hemiparesis, but with antigravity movement. A multidisciplinary team involving Pediatric Oncology, Pediatric Neurology, Neurosurgery, Pathology, Radiation Oncology, and Rehabilitation Medicine is essential for patients with rare central nervous system tumors, to maximize effective treatment strategies despite limited resources.
Coaxially Fabricated Dual‐Drug Loading Electrospinning Fibrous Mat with Programmed Releasing Behavior to Boost Vascularized Bone Regeneration
Authors: Jinjie Cui, Xingge Yu, Bin Yu, Xiuyi Yang, Zeyu Fu, Jianyu Wan, Min Zhu, Xudong Wang, Kaili Lin
Journal: Advanced Healthcare Materials (2022)

Abstract In clinical treatment, the bone regeneration of critical‐size defects is desiderated to be solved, and the regeneration of large bone segment defects depends on early vascularization. Therefore, overcoming insufficient vascularization in artificial bone grafts may be a promising strategy for critical‐size bone regeneration. Herein, a novel dual‐drug programmed releasing electrospinning fibrous mat (EFM) with a deferoxamine (DFO)‐loaded shell layer and a dexamethasone (DEX)‐loaded core layer is fabricated using coaxial electrospinning technology, considering the temporal sequence of vascularization and bone repair. DFO acts as an angiogenesis promoter and DEX is used as an osteogenesis inducer. The results demonstrate that the early and rapid release of DFO promotes angiogenesis in human umbilical vascular endothelial cells and the sustained release of DEX enhances the osteogenic differentiation of rat bone mesenchymal stem cells. DFO and DEX exert synergetic effects on osteogenic differentiation via the Wnt/ β ‐catenin signaling pathway, and the dual‐drug programmed releasing EFM acquired perfect vascularized bone regeneration ability in a rat calvarial defect model. Overall, the study suggests a low‐cost strategy to enhance vascularized bone regeneration by adjusting the behavior of angiogenesis and osteogenesis in time dimension.
Activating MET kinase domain mutations define a novel molecular subtype of non–small cell lung cancer that is clinically targetable with the MET inhibitor elzovantinib (TPX-0022).
Authors: Federica Pecci, Biagio Ricciuti, Joao Victor Machado Alessi, Adriana Paula de Castro Barrichello, Victor R. Vaz, Giuseppe Lamberti, Jessica Kim Lee, Alexa Betzig Schrock, Vikas K Goel, Zach Zimmerman, Magda Bahcall, Pasi A. Janne, Mark M. Awad
Journal: Journal of Clinical Oncology (2022)

9124 Background: In non-small cell lung cancer (NSCLC), MET exon 14 skipping (METex14) mutations and MET amplification can be targeted with MET inhibitors. Here, we describe a novel, actionable molecular subtype of NSCLC characterized by activating MET-tyrosine kinase domain (MET-TKD) mutations in the absence of METex14 mutations. Methods: Clinicopathologic and genomic data were abstracted from NSCLC cases included in a multi-institutional cohort of tumors that underwent genomic profiling in the GENIE v10, China PanCancer, and the International Cancer Genome Consortium/ The Cancer Genome Atlas (ICGC/TCGA) datasets. External validation of the prevalence of MET-TKD mutations was performed on an independent cohort of NSCLC tissue and liquid samples from the Foundation Medicine genomic database. Results: Among 14,099 NSCLC samples in the multi-institutional cohort, 71 (0.5%) harbored MET-TKD mutations without concurrent METex14 mutations: 55 of these had uncertain pathogenic significance and 16 had known oncogenic potential, including MET H1094Y/R, D1228H/N/V, N1100S, H1106D, V1188I, and M1250T, in order of decreasing prevalence. In a separate cohort of 91,515 NSCLC samples from the Foundation Medicine database, MET-TKD mutations lacking concurrent METex14 mutations were identified in 799 (0.9%) samples, including H1094Y, L1195V, D1228H/N, M1250T and others. Among 60 NSCLC samples harboring MET-TKD mutations without concurrent METex14 mutations with complete genomic data in the multi-institutional cohort, 36 (60%) had concurrent driver alterations in KRAS, EGFR, ROS1, BRAF, HER2, or RET, while 24 (40%) had no concurrent oncogenic drivers. Among patients with available demographic data in the multi-institutional cohort, those with MET-TKD-mutant NSCLC (N = 70) were significantly younger than patients with METex14-mutant NSCLC (N = 353) (median age 63 [range 30-86] vs 73 [range 44-88], p &lt; 0.0001), and there was no significant difference in sex or self-reported race. Confirmed partial responses to the MET tyrosine kinase inhibitor elzovantinib (TPX-0022) were observed in two patients with MET-TKD-mutant NSCLC and no other detectable driver mutations: a 64-year-old man with MET H1094Y-mutant NSCLC, and an 80-year-old man with MET F1200I-mutant NSCLC. Conclusions: Potentially actionable MET-TKD mutations lacking concurrent METex14 mutations represent a novel genomic subtype in 0.5-0.9% of NSCLC, and occur in the absence of other known drivers in a subset of cases.
Third-party punishment by preverbal infants
Authors: Yasuhiro Kanakogi, Michiko Miyazaki, Hideyuki Takahashi, Hiroki Yamamoto, Tessei Kobayashi, Kazuo Hiraki
Journal: Nature Human Behaviour (2022)

Third-party punishment of antisocial others is unique to humans and seems to be universal across cultures. However, its emergence in ontogeny remains unknown. We developed a participatory cognitive paradigm using gaze-contingency techniques, in which infants can use their gaze to affect agents displayed on a monitor. In this paradigm, fixation on an agent triggers the event of a stone crushing the agent. Throughout five experiments (total N = 120), we show that eight-month-old infants punished antisocial others. Specifically, infants increased their selective looks at the aggressor after watching aggressive interactions. Additionally, three control experiments excluded alternative interpretations of their selective gaze, suggesting that punishment-related decision-making influenced looking behaviour. These findings indicate that a disposition for third-party punishment of antisocial others emerges in early infancy and emphasize the importance of third-party punishment for human cooperation. This behavioural tendency may be a human trait acquired over the course of evolution.
Presepsin for the Diagnosis of Neonatal Early-Onset Sepsis
Authors: Chiara Poggi, Ersilia Lucenteforte, Davide Petri, Salvatore De Masi, Carlo Dani
Journal: JAMA Pediatrics (2022)

Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and questionable performance of the common markers of infection. Presepsin was recently proven to be a promising biomarker for the diagnosis of EOS.
Investigation of a COVID-19 outbreak on the Charles de Gaulle aircraft carrier, March to April 2020: a retrospective cohort study
Authors: Franck de Laval, Hervé Chaudet, Olivier Gorgé, Joffrey Marchi, Constance Lacrosse, Aissata Dia, Vanessa Marbac, Bakridine Mmadi Mrenda, Gaëtan Texier, Flavie Letois, Charles Chapus, Véronique Sarilar, Jean-Nicolas Tournier, Anthony Levasseur, Jacques Cobola, Flora Nolent, Fabien Dutasta, Frédéric Janvier, Jean-Baptiste Meynard, Vincent Pommier de Santi
Journal: Eurosurveillance (2022)

BackgroundSARS-CoV-2 emergence was a threat for armed forces. A COVID-19 outbreak occurred on the French aircraft carrier Charles de Gaulle from mid-March to mid-April 2020.AimTo understand how the virus was introduced, circulated then stopped circulation, risk factors for infection and severity, and effectiveness of preventive measures.MethodsWe considered the entire crew as a cohort and collected personal, clinical, biological, and epidemiological data. We performed viral genome sequencing and searched for SARS-CoV-2 in the environment.ResultsThe attack rate was 65% (1,148/1,767); 1,568 (89%) were included. The male:female ratio was 6.9, and median age was 29 years (IQR: 24-36). We examined four clinical profiles: asymptomatic (13.0%), non-specific symptomatic (8.1%), specific symptomatic (76.3%), and severe (i.e. requiring oxygen therapy, 2.6%). Active smoking was not associated with severe COVID-19; age and obesity were risk factors. The instantaneous reproduction rate (Rt) and viral sequencing suggested several introductions of the virus with 4 of 5 introduced strains from within France, with an acceleration of Rt when lifting preventive measures. Physical distancing prevented infection (adjusted OR: 0.55; 95% CI: 0.40-0.76). Transmission may have stopped when the proportion of infected personnel was large enough to prevent circulation (65%; 95% CI: 62-68).ConclusionNon-specific clinical pictures of COVID-19 delayed detection of the outbreak. The lack of an isolation ward made it difficult to manage transmission; the outbreak spread until a protective threshold was reached. Physical distancing was effective when applied. Early surveillance with adapted prevention measures should prevent such an outbreak.
Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome
Authors: Andres Ramirez-Martinez, Yichi Zhang, Marie-Jose van den Boogaard, John R. McAnally, Cristina Rodriguez-Caycedo, Andreas C. Chai, Francesco Chemello, Maarten P.G. Massink, Inge Cuppen, Martin G. Elferink, Robert J.J. van Es, Nard G. Janssen, Linda P.A.M. Walraven-van Oijen, Ning Liu, Rhonda Bassel-Duby, Richard H. van Jaarsveld, Eric N. Olson
Journal: Journal of Clinical Investigation (2022)

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9–mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.